Currently there are three classes of drugs targeting isoprenoid biosynthesis: (1) statins, such as Lipitor, target HMG-CoA reductase, blocking cholesterol biosynthesis; (2) terbinafine blocks the fungi ergosterol biosynthesis
via inhibiting squalene epoxidase; (3) bisphosphonates like Zometa, Fosmax are used for the treatment of bone resorption through inhibiting farnesyl diphosphate synthase. Beyond these drugs, little progress has been made in this field. Our work has contributed to the understanding of the structure, biology, and inhibition of new potential drug targets in this metabolic pathway, opening up intriguing possibilities for new drug (or therapy) discovery.
Selective Achievements
(1) We provided a combination therapy for Kras-driven cancers using rapamycin and a mevalonate pathway inhibitor;
(2) For malaria, we confirmed
Plasmodium geranylgeranyl diphosphate synthase a drug target for the treatment of malaria and discovered very potent drug leads.
Honors and awards
Tsinghua-Janssen Investigator Award （2015）
Tsinghua-Janssen Investigator Award (2014)
American Heart Association Fellowship (2006)
Yufeng-Hou Scholarship (1996)
Selected publications
1. Xia, Y., Xie, Y., Yu, Z., Xiao, H., Jiang, G., Zhou, X., Yang, Y., Li, X., Zhao, M., Li, L., Zheng, M., Han, S., Zong, Z., Meng, X., Deng, H., Ye, H., Fa, Y., Wu, H., Oldfield, E., Hu, X., Liu, W*., Shi, Y*.,
Zhang, Y
*. The mevalonate pathway is a druggable target for vaccine adjuvant discovery.
Cell
,
2018
,
175
, 1059-1073.
2. Yang, Y., Li, L., Zhou, X., Duan, J., Liu, W., Chen, C., Wang, L., Li, X., Cai, N., Yuan, L., Chen, J., Kang, N., Malwal, S.R., Shi, Y., Oldfield, E*., Guo, R-T*.,
Zhang, Y
*. A structural change in butyrophilin upon phosphoantigen binding underlies phosphoantigen-mediated Vγ9Vδ 2 T cell activation.
Immunity
, 2019
, 50
, 1043-1053.
3. Cai, N., Han, S.,
Zhang, Y*.
Docking complete: a step further toward the holy grail of γδ T cell biology.
Immunity
, 2019,
51
, 781-783.
4. Han, S., Li, X., Xia, Y., Yu, Z., Cai, N., Malwal, S., Han, X., E. Oldfield*.,
Zhang, Y*
. Farnesyl pyrophosphate synthase as a target for drug development: discovery of natural-product-derived inhibitors and their activity in pancreatic cancer cells.
J. Med. Chem.
2019,
62
, 10867-10896.
5. Malwal, S.R., Gao, J., Hu, X., Yang, Y., Liu, W., Huang, J., Ko, T-Z., Li, L., Chen, C., O’Dowd, B., Khade, R., Zhang, Y.,
Zhang, Y
*., Oldfield, E*., Guo, R-T*. Catalytic role of conserved asparagine, glutatmine, serine, and tyrosine residues in isoprenoid biosynthesis enzymes.
ACS Catalysis
. 2018,
8
, 4299-4312.
6. Wang, Y., Chen, C-C., Yang, Y., Liu, W., Ko, T-P., Shang, N., Hu, X., Xie, Y., Huang, J-W.,
Zhang,Y
*., Guo, R*. Structural insight into a novel indole prenyltransferase in hapalindole-type alkaloid biosynthesis.
Biochem. Biphys. Res. Commun.
2018,
495
, 1782-1788.
7. Chen, C-C., Hu, X., Tang, X., Yang, Y., Ko, T-Z., Gao, J., Zheng, Y., Huang, J., Yu, Z., Li, L., Han, S., Cai, N.,
Zhang, Y
*., Liu, W*., Guo, R-T*. Crystal structure of a new class of cyclases which catalyze Cope rearrangement.
Angew. Chem. Int. Ed
. 2018,
57
, 15060-15064.
8. Zhou, X., Gu, Y., Xiao, H., Kang, N., Xie, Y., Zhang, G., Shi, Y., Hu, X., Oldfield, E., Zhang, X*.,
Zhang, Y
*. Combining Vγ9Vδ2 T cells with a lipophilic bisphosphonate efficiently kills activated hepatic stellate cells.
Front. Immunol.
2017,
8
, 1381.
9. Xia, Y., Liu, Y-L., Xie, Y., Zhu, W., Guerra, F., Shen, S., Yeddula, N., Fischer, W., Low, W., Zhou, X.,
Zhang, Y
*., Oldfield, E*., Verma, I. M*. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.
Sci. Trans. Med
.
2014
，263ra261.
